Bubble cloud characteristics and ablation efficiency in dual-frequency intrinsic threshold histotripsy

Histotripsy is a non-thermal focused ultrasound ablation method that destroys tissue through the generation and activity of acoustic cavitation bubble clouds. Intrinsic threshold histotripsy uses single-cycle pulses to generate bubble clouds when the dominant negative pressure phase exceeds an intrinsic threshold of ∼25-30 MPa. The ablation efficiency is dependent upon the size and density of bubbles within the bubble cloud. This work investigates the effects of dual-frequency pulsing schemes on the bubble cloud behavior and ablation efficiency in intrinsic threshold histotripsy. A modular 500 kHz:3 MHz histotripsy transducer treated agarose phantoms using dual-frequency histotripsy pulses with a 1:1 pressure ratio from 500 kHz and 3 MHz frequency elements and varying arrival times for the 3 MHz pulse relative to the arrival of the 500 kHz pulse (-100 ns, 0 ns, and +100 ns). High-speed optical imaging captured cavitation effects to characterize bubble cloud and individual bubble dynamics. The effects of dual-frequency pulsing on lesion formation and ablation efficiency were also investigated in red blood cell (RBC) phantoms. Results showed that the single bubble and bubble cloud size for dual-frequency cases were intermediate to published results for the component single-frequencies of 500 kHz and 3 MHz. Additionally, bubble cloud size and dynamics were shown to be altered by the arrival time of the 3 MHz pulse with respect to the 500 kHz pulse, with more uniform cloud expansion and collapse observed for early (-100 ns) arrival. Finally, RBC phantom experiments showed that dual-frequency exposures were capable of generating precise lesions with smaller areas and higher ablation efficiencies than previously published results for 500 kHz or 3 MHz. Overall, results demonstrate dual-frequency histotripsy's ability to modulate bubble cloud size and dynamics can be leveraged to produce precise lesions at higher ablation efficiencies than previously observed for single-frequency pulsing.